Crystalline form VII of cabergoline

ABSTRACT

Crystalline form VII of cabergoline, a pharmaceutical composition containing it and a process for its preparation are disclosed. The process may comprise a slurry procedure using form I or mixture of forms I and VII of cabergoline in a solvent at a temperature above 30° C.

The present invention concerns a new crystalline form of cabergoline, apharmaceutical composition thereof and its use as therapeutically activeagent, alone or in combination. Another aspect of the present inventionrelates to the preparation of this crystalline form. Cabergoline is anergoline derivative interacting with D2 dopamine receptors and isendowed with different useful pharmaceutical activities and it is usedin the treatment of hyperprolactinemia, central nervous system disorders(CNS) and other related diseases.

Cabergoline is the generic name of1((6-allylergolin-8beta-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea,described and claimed in U.S. Pat. No. 4,526,892. The synthesis ofCabergoline molecule is reported also in European. J. Med. Chem.,24,421, (1989) and in GB-2,103,603-B.

During our work we discovered that cabergoline can exist in at least twocrystalline forms under ambient conditions. One form (coded Form I) isan anhydrous not solvated form and, to our knowledge, it is the onlyform reported in the literature to date. Form VII is an anhydrous notsolvated form too.

Thus, the present invention concerns a new polymorph (Form VII) ofcabergoline and the preparation thereof. Another aspect relates tosamples of cabergoline Form VII having a % polymorphic purity>90%,preferably >99%. The invention further provides a pharmaceuticalcomposition of cabergoline Form VII and its use as therapeutic agent.

DESCRIPTION OF FIGURES

FIG. 1. XRD powder pattern of cabergoline Form VII.

FIG. 2. DSC curve of cabergoline Form VII.

FIG. 3. IR spectrum of cabergoline Form VII (sample prepared by KBrpowder technique).

FIG. 4. Solid state ¹³C-NMR spectrum of cabergoline form VII.

Form VII is the thermodynamically most stable polymorph in a range oftemperature between +30° and +80° C. It can be readily prepared byslurry of form I or mixture of form I and VII in a solvent at atemperature over 30° C. The importance of cabergoline form VII restsprimarily (but not exclusively) in thermodynamic stability.

Form VII shows advantages with respect to form I because of its greaterstability.

Characterisation

X-ray powder diffraction (XRD), differential scanning calorimetry (DSC),infrared (IR) spectroscopy and solid state ¹³C-NMR were used tocharacterise the new form.

X-Ray Powder Diffraction

Powder X-ray diffraction was performed using either a Scintag X1 or X2Advanced Diffraction System operating under Scintag DMS/NT© Ver 1.30aand 1.36b respectively, and Microsoft Windows NT 4.0™ software. Thesystem used a copper X-ray source maintained at 45 kV and 40 mA toprovide CuKα₁ emission of 1.5406 angstroms and a solid state peltiercooled detector. Beam aperture was controlled using tube divergence andanti-scatter slits of 2 and 4 mm and detector anti-scatter and receivingslits of 0.5 and 0.3 mm width. Data were collected from 2 to 40°two-theta using a step scan of 0.03°/point with a one second/pointcounting time. The samples were hand ground using a pestle and mortarand packed into an aluminum sample tray with a 12 mm (diam.)×0.5 mmcavity.

DSC

Measurements of differential scanning calorimetry were obtained on aMettler TA 4000 thermal analysis system. Approximately 8.5 mg sampleswere accurately weighed into a DSC Pan. The pans were hermeticallysealed and a pinhole was punched into the Pan lid. The use of thepinhole allows for pressure release, but still assures that the thermalreactions proceed under controlled conditions. The samples wereintroduced into the DSC oven and then heated at a rate of 5° C./min, upto a final temperature of 135° C.

IR Spectroscopy

IR spectrum of cabergoline form VII was obtained on a Perkin Elmer FT-IRspectrophotometer PARAGON 1000. The sample was prepared by KBr powdertechnique registering the spectrum on reflectance.

Solid State ¹³C-NMR

Solid state ¹³C-NMR spectra were obtained on a MSL 300 Bruker instrumentequipped with solid state facilities and variable temperature magicangle spinning probe. Cross polarisation experiments were performed by adecoupling field of 50 KHz and single pulse magic angle spinningexperiments with recycle times ranging from 10 to 100 records.

The XRD, DSC, IR and NMR curves are shown in FIGS. 1-4 respectively.

The x-ray powder diffraction pattern for Form VII (FIG. 1) shows acrystalline structure with useful distinctive peaks at approximately5.6, 8.1, 10.6 and 10.8° 2-theta. The DSC curve of Form VII (FIG. 2)exhibits a melting endotherm at approximately 121° C. The integratedmelting endotherm has a heat of fusion of approximately 60 J/g.

The IR spectrum of Form VII is shown in FIG. 3.

The solid state ¹³C-NMR spectrum of form VII is shown in FIG. 4.

These data indicate that cabergoline Form VII is a crystalline polymorpheasily distinguishable from form I by XRD, DSC and solid state ¹³C-NMRtechniques. IR, combined with another analytical technique, is anothermethod to distinguish the two polymorphs. The difference is a band inthe region of 3500 cm⁻¹ that appears like a shoulder of a greatersignal.

Crystalline cabergoline I has been reported in Il Farmaco, 50 (3),175-178 (1995). However, to applicants' knowledge, no one has reportedany other crystalline form.

In summary, cabergoline exists in at least two crystalline forms. Form Iis a crystal (melting point=98°-105° C. by DSC, heat of fusion of _(˜)60J/g) with a characteristic powder XRD pattern and ¹³C-NMR spectrum.

Form VII is a crystalline (melting point=121° C. by DSC, heat of fusionabout 60 J/g) with characteristic powder XRD pattern and ¹³C-NMRspectrum. DSC too is very different from that of form I.

The present invention also provides a process for producing crystallinecabergoline Form VII by subjecting crystals of form I or a mixture ofcrystals form I and VII to a slurry procedure at a temperature over 30°C. Preferably, the process comprises suspending crystals of form I or amixture of crystals form I and VII in an organic solvent, such asn-heptane, diethyl ether, or n-hexane, at a temperature of from +30° to+80° C., more preferably about 55° C. The resultant suspension is thenstirred at this temperature for about from 24 to 120 hours, morepreferably for about 48 hours.

The thus obtained crystals of Form VII may be recovered by commonprocedures, for example by filtration under reduced pressure or bycentrifugal filtration, followed by drying the crystals, to obtain thecrystalline Form VII cabergoline of the present invention. Likecabergoline Form I, Forms VII displays a significant inhibitory effectwith regard prolactine and has therapeutic properties that make itpossible to treat patients who have pathological conditions associatedwith an abnormal prolactin level, thus is useful in human and/orveterinary medicine.

Cabergoline is also active, alone or in combination, in the treatment ofreversible obstructive airways diseases, for controlling intraocularpressure and for the treatment of glaucoma. It is also employed in theveterinary field, as antiprolactin agent and in cutting down drasticallythe proliferation of vertebrate animals. The several uses of cabergolineare for example described in WO9948484, WO9936095, U.S. Pat. No.5,705,510, WO9505176, EP040325.

Forms VII in accordance with the invention is particularly useful in thetreatment of Parkinson's disease (PD), Restless Legs Syndrome (RLS),treatment of diseases like Progressive Supranuclear Palsy (PSP) andMultysystemic atrophy (MSA). Thus, another aspect of the instantinvention concerns a method for treatment of Parkinson's disease (PD),Restless Legs Syndrome (RLS), Progressive Supranuclear Palsy (PSP) andMultysystemic atrophy (MSA) which comprises administering to a host aneffective amount of cabergoline Form VII.

Cabergoline Forms VII of the present invention may be used in a mannersimilar to that of cabergoline Form I; therefore, a person skilled inthe art of CNS diseases treatment will be able to ascertain, withoutundue experimentation, an appropriate treatment protocol foradministering a compound of the present invention. The dosage, mode andschedule of administration for compounds of this invention are notparticularly restricted, and will vary with the particular compoundemployed. Thus Forms VII of the present invention may be administeredvia any suitable route of administration, preferably orally. For CNSdiseases treatment, the dosage may be, for example, in the range ofabout 0.5 to about 50 mg/patient/day, preferably 2 to 4 mg daily asmonotherapy and 2 to 6 mg daily as adjuvant therapy. The actual doseused will vary according to the particular composition formulated, theroute of administration, and the particular disease being treated. Manyfactors that modify the action of the drug will be taken into account indetermining the dosage including age, weight, sex, diet and the physicalcondition of the patient.

The present invention also provides pharmaceutical compositions(formulations) containing an effective amount of Form VII in combinationwith one or more pharmaceutically acceptable carriers, excipients,diluents or adjuvants.

For example, Form VII invention may be formulated in the form oftablets, pills, powder mixtures, capsules, injectables, solutions,suspensions, suppositories, emulsions, dispersions, food premix, and inother suitable forms. It may also be manufactured in the form of sterilesolid compositions, for example, freeze dried and, if desired, combinedwith other pharmaceutically acceptable excipients. Such solidcompositions can be reconstituted with sterile water, physiologicalsaline, or a mixture of water and an organic solvent, such as propyleneglycol, ethanol, and the like, or some other sterile injectable mediumimmediately before use for parenteral administration as a suspension(microdispersion) or in solution. Typical of pharmaceutically acceptablecarriers are, for example, manitol, urea, dextrans, lactose, potato andmaize starches, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate,ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate,gelatin, potassium carbonate, silicic acid. The pharmaceuticalpreparation may also contain nontoxic auxiliary substances such asemulsifying, preserving, wetting agents, and the like as for example,sorbitan monolaurate, triethanolamine oleate, polyoxyethylenemonostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, andthe like.

Example 1

55.5 g of crystalline cabergoline form I were added to 700 ml ofn-heptane at 55° C. The suspension was stirred at this temperature forabout 48 hours and then filtered using a glass filter under vacuum. Theresulting crystals were dried under vacuum at 40° C. for 24 hours. Afterdrying the resultant crystal form VII was identified by XRD, DSC, IR andNMR, data shown in FIGS. 1-4 respectively, having polymorphicpurity>99%.

Example 2

27.65 g of cabergoline were dissolved in 1,4-dioxane at 40° C.; thefinal solution (68 mL) was slowly cooled till to −5° C., in stirring.After 24 hours the obtained solid was filtered on sintered-glass G4filter and then dried at from 30° C. to 65° C. under N₂ and vacuum. Theresultant crystals form VII were identified by DSC and IR. Yield was45.2%.

What is claimed is:
 1. Crystalline form VII of cabergoline. 2.Crystalline form VII of cabergoline according to claim 1 which isanhydrous, non-solvated and has a percentage purity greater than 92%. 3.Crystalline form VII of cabergoline according to claim 1 which isanhydrous, non-solvated and has a percentage purity greater than 99%. 4.Crystalline form VII of cabergoline according to claim 1 having the XRDpowder pattern of FIG.
 1. 5. A pharmaceutical composition whichcomprises an effective amount of crystalline Form VII, as defined inclaim 1 in combination with one or more pharmaceutically acceptablecarriers, excipients, diluents or adjuvants.
 6. A process for producingcabergoline Form VII as defined in claim 1, which process comprisessubjecting crystals of form I, or a mixture of forms I and VII, ofcabergoline to a slurry procedure at a temperature above 30° C.,followed by recovery and drying of the resulting crystals.
 7. A processaccording to claim 6 in which the slurry procedure comprises suspendingcrystals of form I or a mixture of forms I and VII of cabergoline in anorganic solvent, at a temperature of from +30° to +80° C., and stirringthe resultant suspension for from 24 to 120 hours.
 8. A processaccording to claim 7 in which the solvent is diethyl ether, n-heptane orn-hexane.
 9. A pharmaceutical composition which comprises an effectiveamount of crystalline Form VII, as defined in claim 2 in combinationwith one or more pharmaceutically acceptable carriers, excipients,diluents or adjuvants.
 10. A pharmaceutical composition which comprisesan effective amount of crystalline Form VII, as defined in claim 3 incombination with one or more pharmaceutically acceptable carriers,excipients, diluents or adjuvants.
 11. A pharmaceutical compositionwhich comprises an effective amount of crystalline Form VII, as definedin claim 4 in combination with one or more pharmaceutically acceptablecarriers, excipients, diluents or adjuvants.
 12. A process for producingcabergoline Form VII as defined in claim 2, which process comprisessubjecting crystals of form I, or a mixture of forms I and VII, ofcabergoline to a slurry procedure at a temperature above 30° C.,followed by recovery and drying of the resulting crystals.
 13. A processfor producing cabergoline Form VII as defined in claim 3, which processcomprises subjecting crystals of form I, or a mixture of forms I andVII, of cabergoline to a slurry procedure at a temperature above 30° C.,followed by recovery and drying of the resulting crystals.
 14. A processfor producing cabergoline Form VII as defined in claim 4, which processcomprises subjecting crystals of form I, or a mixture of forms I andVII, of cabergoline to a slurry procedure at a temperature above 30° C.,followed by recovery and drying of the resulting crystals.